Therapeutic methods of employing hydrogen maleate salt of n-(d-6-methyl-8-isoergolenyl)-n{40 ,n{40 -diethyl-carbamide

ABSTRACT

Method of using N-(D-6-methyl-8-isoergolenyl)-N&#39;&#39;, N&#39;&#39;diethylcarbamide hydrogen maleate in the therapeutic treatment of migraine headache, urticaria, hypertension and allergic conditions, in the last case along or in the form of an enhanced effect when administered together with an anti-histamine.

ilnited States atent Semonsky et a1.

[54] THERAPEUTIC METHODS OF EMPLOYING HYDROGEN MALEATE SALT OFN-(D-6-METHYL-8- ISOERGOLENYL)-N,N'-DIETHYL- CARBAMIDE [72] Inventors:Miroslav Semonsky'; Viktor Zikan,

both of Prague, Czechoslovakia [73] Assignee: Spofa Spojene Podniky ProZdravotnick-on Vyrobu, Prague, Czechoslovakia [22] Filed: May 25, 1967[21] Appl. No.2 641,160

[30] Foreign Application Priority Data June 7, 1966 Czechoslovakia..3860/66 [52] US. Cl ..424/261 [51] Int. Cl. ..A6lk 27/00 [58] Field ofSearch ..424/261; 260/285.5

[56] References Cited UNITED STATES PATENTS 3,218,324 11/1965 Hofmann etal. ..424/261 3,228,944 l/l966 Bernardi et a1. ..260/285.5

3,238,211 3/1966 Camerino et al. ..260/285.5

FOREIGN PATENTS OR APPLICATIONS 100,832 9/1961 Czechoslovakia OTHERPUBLICATIONS Rysanek et al.; Chem Abst. Vol 63 (1965) page 6221h IVotava et al.; Chem Abst. Vol. 59 (1963), Page 9221d Votava et al.;Chem. Abst. Vol. 62 (1965) page 15307h etc.

Cerny et al.; Chem. Abst. Vol. 59 (1963) page 7581d etc.

Spofa; Chem. Abst. Vol. 57 (1962) page 15005f Grollman; Pharmacology andTherapeutics, 1965, Publisher Lea & Febiger, pages 244- 247 PrimaryExamine rSam Rosen Att0rneyMichael S. Striker 5 7 ABSTRACT Method ofusing N-(D-6-methyl-8-isoergolenyl)-N, N'-diethylcarbamide hydrogenmaleate in the therapeutic treatment of migraine headache, urticaria,hypertension and allergic conditions, in the last case along or in theform of an enhanced effect when administered together with ananti-histamine.

6 Claims, No Drawings N-CH COOH

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Clinical tests carried out with Lysenyl establish that the sameconstitutes a specific serotonin antogonist and can be employed as amedicament in those conditions and diseases, caused or aggravated byserotonin.

It has also been established by appropriate pharmacological tests thatthe administration of Lysenyl as compared with analogous preparationsproduces little or no undesirable side effects i.e., the compound in thefree base form or salt form is substantially non-toxic.

The following table represents the data obtained in taxicity studieswith Lysenyl.

TOXICITY OF LYSENYL Acute Toxicity:

D i.v. s.c. oral mice 14.4 mg/kg 82 mg/kg 90 mg/kg rats 1.5 mg/kg 3mg/kg 12.5 mg/kg It has been established that the clinical therapeuticoral dose of Lysenyl for humans amounts to 0.00125 mg/kg daily and istherefore about a l/70,000 (one seventy-thousandth part) of the oral LDin mice, or about 1/ 10,000 (one ten-thousandth part) of thecorresponding dose in rats.

Chronic Toxicity The chronic toxicity was investigated in rats whichreceived daily doses of 0.005 mg/kg or 0.025 mg/kg s.c. for three monthsand in a second series of tests, the same doses for 6 months. Dataobtained at the conclusion of these tests, when compared with the datafrom the control animals, did not reveal any alterations which could beregarded as signs of undesirable or toxic effects of Lysenyl. The dataincluded blood counts, biochemical determinations, histological studies, growth studies, etc.

The administration of daily oral doses of 0.01 mg/kg to pregnant ratsfor the entire duration of the pregnancy did not cause any significantincrease of the incidence of fetus resorption. The delivered ofispringwere alive and free from developmental abnormalities.

The following clinical studies were carried out in order to evaluate theeffectiveness of Lysenyl. a. Migraine A comprehensive evaluation ofresults obtained in several different clinics with the therapeuticadministration of Lysenyl in cases of vascular headache of themigraineous type was carried out. The evaluation establishes that in asample comprising 144 patients the following results are obtained:

1. in 73 (50.7 percent) of the patients, either a complete disappearanceof migraineous attacks, or a very substantial amelioration (a verymarked decrease of the intensity and frequency of the attacks);

2. in 47 (32.6 percent) patients, an amelioration;

3. in 24 (16.7 percent) patients, no apparent effect.

A beneficial efiect was therefore observed in approximately 83 percentof patients.

The preparation was administered orally in a very low dosage, on theaverage 25 mcg was administered twice daily, at the most 25 mcg wasgiven three times daily. This dosage is only l/40th of that usuallygiven for methysergide, making Lysenyl a more effective preparation withrespect to the dosage necessary to produce the desired action whencompared to the most widely heretofore used preparation. Lysenyl,similarly to methysergide, is suited for long-term therapy but not forthe suppression of an attack already developed.

b. Allergic Conditions In accordance with the recently establishedconcepts of the participation of serotonin in the pathogenesis ofallergic conditions, Lysenyl was also evaluated in various allergicdiseases (urticaria and Quinckes edema, eczema, bronchial asthma,vasomotor rhinitis, etc.), and mostly in such cases which were resistantagainst the usual antiallergic therapy (antihistamines,desensitization). The dosage used amounted to 25 mcg twice to threetimes daily. The obtained results were very good, in some cases evensurprising, specifically when Lysenyl was administered together i.e., incombination with known antihistamines and thus the combined therapeuticactivities of the respective components, i.e., the antihistamine and theantiserotonin effect, could be brought about at the same time. The bestresults were achieved in the urticaria and Quinckes edema while theeflect in vasomotoric rhinitis was relatively weaker.

The antiallergic effectiveness of Lysenyl was further established by thepreventive oral administration of 25mcg of the drug three-fourths to 1hour before intracutaneous testing of inhalation allergens. Incomparison with the control group, a partial inhibition of the localreaction was observed. The average diameter of the local reaction areolawas diminished by 7.8 mm (Lysenyl 11.0 mm, control 18.8 mm).

c. The Dumping Syndrome The symptoms of the post-resection syndrome,especially the increased rate of intestinal passage, can be consideredas consequences of an increased production and release of serotonin inthe small intestine. In accordance with this concept, Lysenyl wasadministered in preliminary trials to 9 patients, following surgery forresection of the stomach, and who suffered from a pronouncedpost-resection syndrome. These outpatients received low doses during thefirst week which were gradually increased thereafter to doses of 75 200mcg daily. The therapeutic effect manifested itself as early as after 24hours in 6 patients of the 9 by a suppression of the diarrhea, and inthe course of the first week of the therapy, the condition of twofurther patients improved. The patients noted that at the same time asthe frequency of stools diminished, the disappearance of the feeling ofabdominal tension, an increase of the appetite, and an improvement ofboth physical and psychical condition.

Tolerability. In a long-term clinical study aimed at the pharmacologicalinvestigation of Lysenyl, the preparation was administered to 56hypertensive patients for 3 14 months. The initial dosage, l2.5 mcgdaily, was gradually increased to an average dosage of 25 mcg threetimes daily. in all patients, the following analyses were carried outbefore the treatment, once a month during treatment, and three monthsafter termination of treatment; examination of the urine and urinesediment, creatinine clearance, non-protein nitrogen, blood count,sedimentation of erythrocytes, and electro-cardiogram.

in 26 patients treated for more than 6 months, at the intervals setforth above, the following additional analyses were carried out: serumbilirubin, thymol turbidity reaction, SGPT (serum glutamate-pyruvatetransarninase) phosphatase, and glycernia on an empty stomach.

In 8 patients treated for more than 8 months, the renal blood flow(clearance of para aminohippuric acid) and the glomerular filtrationrate (clearance of inulin) were determined before and after thetreatment in addition to all of the above recited analyses.

All values established throughout the testing were compared with thosevalues found before the treatment and were found to have remainedwithout pathological changes. In the majority of those patients who hadhad proteinuria before the treatment, the latter disappeared completelyin the course of the therapy.

Blood pressure decreased during the monotherapy with Lysenyl especiallyin patients in the initial stages of hypertension marked by a moderatelyhigh diastolic pressure. During treatment a number of subjectivecomplaints either disappeared or were substantially alleviated,especially headache and cephalernia. A comprehensive evaluation ofreports from all of the clinical studies carried out reveals that sideeffects were ob served in about percent of cases. The most frequent sideeffects were nausea, a feeling of lassitude, nasal stifiiness, anddryness in the mouth; less frequent side effects were vomiting or aslight vertigo. Diarrhea was encountered only sporadically (in patientswith migraine and allergy). Headache was seen only infrequently (inthose patients with the dumping syndrome). All these side effects weretransient and disappeared as soon as the dosage had been decreased. Onlyin quite exceptional cases did the therapy have to be discontinued. Themajority of the observed side effects developed in such cases where thetherapy had been started with a full dosage (25 mcg three times daily),and their frequency fell to a minimum when the optimum dosage scheme wasused, i.e., when the dosage was gradually increased.

In comparison to the frequency of undesirable side effects seen with theuse of methysergide, the side effects of Lysenyl are sigiificantly lessin number and severity.

The following Examples illustrate pharmaceutical preparations for use inthe practice of this invention, but the same are not to be consuued as alimitation thereof.

EXAMPLE 1 Tablets of the formula:

milligram Lysenyl 0.025 Lactose 97.875 Corn starch l 1.00 Magnesiumstearate 1.1

Total weight 110.000

Tablets were prepared according to the usual procedure for thepreparation of tablets for pharmaceutical use.

EXAMPLE II The dosage used in combination of Lysenyl withantihistamines; Lysenyl 25 mcg Bromadryl mebrophenhydraminehydrochloride) 25 mg twice to threev times daily, or Lysenyl 25 mcgMedrin mebrophenhydrinate) 25 mg twice to three times daily.

The results of the clinical tests permit the following conclusions:

1. Lysenyl is, with respect to the size of the clinically effectivedosage, the most active of the known serotonin antagonists.

2. it is the drug of choice for the long-term therapy of vascularheadache of the migraine type.

3. In allergic conditions, it substantially enhances, by

its antiserotonin activity, the therapeutical usefulness ofantihistamines.

4. In the dumping syndrome it exerts a reliable blocking effect upon theuntoward action of serotonin on the intestinal motility.

5. Side effects observed during the therapy with Lysenyl are, incomparison with analogous preparations, both of less intensity and oflesser frequency and they are practically negligible if an appropriatedosage scheme is used.

We claim:

I. A method of relieving vascular headaches of a pa tient suffering frommigraine which comprises administering to such patientN-(D-6-methyl-8-isoergolenyl)-N,N'-diethyl-carbamide hydrogen maleate ina dose of 25 mcg two to three times daily, said N-(D-6-methyl-8-isoergolenyl )-N' ,N -diethylcarbamide hydrogen maleate actingas a specific serotonin antagonist to excessive production of serotonin.

2. A method of treating a patient for suppressing or mitigating thedevelopment of allergic reactions to an allergic stimulus whichcomprises orally administering to such patientN-(D-6-methyl-8-isoergolenyl)- N, N-

diethyl-carbamide hydrogen maleate in a dose of 25 mcg two to threetimes daily, said N-(D-6-methyl-8- isoergolenyl)--N,N-diethyl-carbamidehydrogen maleate acting as a specific sertonin antagonist to excessiveproduction of serotonin.

3. A method of treating a patient for suppressing or mitigating thedevelopment of urticaria or Quinckes edema in response to an allergicstimulus which comprises orally administering to such patient N-(D-6-methyl- 8-isoergolenyl )-N' ,N -diethyl-carbarnide hydrogen maleate in adose of 35 mcg two to three times daily, saidN-(D-6-methyl-8-isoergolenyl)-N,N- diethyl-carbamide hydrogen maleateacting as a specific serotonin antagonist to excessive production ofsertonin.

4. Method according to claim 3 wherein said N-(D-6-methyl-S-isoergolenyl)-N',N'-diethyl-carbamide hydrogen maleate isadministered together with 25 mg of another antihistamine, each of saidagents being administered two to three times daily, said N-(D-6-methyl-S-isoergolenyl )-N' ,N'-diethyl-carbamide hydrogen maleate actingas a specific serotonin antagonist to excessive production of serotonin.

5. Method according to claim 4 wherein said antihistamine is a memberselected from the group consisting of mebrophenhydramine andmebrophenhydrinate.

6. A method of treating hypertension which com prises orallyadministering to a hypertensive patient N-(D-6-methyl-8-isoergolenyl)-N',N-diethyl-carbamide hydrogen maleate in adosage of about 25 mcg twice daily, saidN-(D6-methyl-8-isoergolenyl)-N',N- diethyl-carbamide hydrogen maleateacting as a specific serotonin antagonist to excessive production ofserotonin.

2. A method of treating a patient for suppressing or mitigating thedevelopment of allergic reactions to an allergic stimulus whichcomprises orally administering to such patientN-(D-6-methyl-8-isoergolenyl)- N'', N''-diethyl-carbamide hydrogenmaleate in a dose of 25 mcg two to three times daily, saidN-(D-6-methyl-8-isoergolenyl)--N'',N''-diethyl-carbamide hydrogenmaleate acting as a specific sertonin antagonist to excessive productionof serotonin.
 3. A method of treating a patient for suppressing ormitigating the development of urticaria or Quincke''s edema in responseto an allergic stimulus which comprises orally administering to suchpatient N--(D-6-methyl-8-isoergolenyl)-N'',N''-diethyl-carbamidehydrogen maleate in a dose of 35 mcg two to three times daily, saidN-(D-6-methyl-8-isoergolenyl)-N'',N''-diethyl-carbamide hydrogen maleateacting as a specific serotonin antagonist to excessive production ofsertonin.
 4. Method according to claim 3 wherein saidN-(D-6-methyl-8-isoergolenyl)-N'',N''-diethyl-carbamide hydrogen maleateis administered together with 25 mg of another antihistamine, each ofsaid agents being administered two to three times daily, saidN-(D-6-methyl-8-isoergolenyl)-N'',N''-diethyl-carbamide hydrogen maleateacting as a specific serotonin antagonist to excessive production ofserotonin.
 5. Method according to claim 4 wherein said antihistamine isa member selected from the group consisting of mebrophenhydramine andmebrophenhydrinate.
 6. A method of treating hypertension which comprisesorally administering to a hypertensive patientN-(D-6-methyl-8-isoergolenyl)-N'',N''-diethyl-carbamide hydrogen maleatein a dosage of about 25 mcg twice daily, saidN-(D-6-methyl-8-isoergolenyl)-N'',N''-diethyl-carbamide hydrogen maleateacting as a specific serotonin antagonist to excessive production ofserotonin.